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Crosstalk Between Apoptosis and Autophagy: Environmental Genotoxins, Infection, and Innate Immunity

View Article: PubMed Central - PubMed

ABSTRACT

Autoimmune disorders constitute a major and growing health concern. However, the genetic and environmental factors that contribute to or exacerbate disease symptoms remain unclear. Type I interferons (IFNs) are known to break immune tolerance and be elevated in the serum of patients with autoimmune diseases such as lupus. Extensive work over the past decade has characterized the role of a protein termed stimulator of interferon genes, or STING, in mediating IFN expression and activation in response to cytosolic DNA and cyclic dinucleotides. Interestingly, this STING-dependent innate immune pathway both utilizes and is targeted by the cell’s autophagic machinery. Given that aberrant interplay between the apoptotic and autophagic machineries contributes to deregulation of the STING-dependent pathway, IFN-regulated autoimmune phenotypes may be influenced by the combined exposure to environmental carcinogens and pathogenic microorganisms and viruses. This review therefore summarizes recent data regarding these important issues in the field of autoimmunity.

No MeSH data available.


Related in: MedlinePlus

Schematic of the stimulator of interferon genes (STING)– dependent innate immune response pathway. The infection of host cells by viruses and microbial pathogens results in the presence of nonself DNA or cyclic dinucleotides in the cytosol of the infected cells. The recognition of this DNA by the enzyme cyclic GMP-AMP synthase (cGAS) induces it to produce the cyclic dinucleotide cGAMP (cyclic GMP-AMP). Both cGAMP and other pathogen-derived cyclic dinucleotides bind STING, which alters the conformation of the protein and allows it to facilitate the phosphorylation of interferon regulatory factor 3 (IRF3) by TANK-binding kinase 1 (TBK1). Interferon regulatory factor 3 phosphorylation induces protein dimerization and entry into the nucleus, where it acts as a transcription factor to drive interferon (IFN) expression. ER indicates endoplasmic reticulum.
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f1-10.1177_1179670716685085: Schematic of the stimulator of interferon genes (STING)– dependent innate immune response pathway. The infection of host cells by viruses and microbial pathogens results in the presence of nonself DNA or cyclic dinucleotides in the cytosol of the infected cells. The recognition of this DNA by the enzyme cyclic GMP-AMP synthase (cGAS) induces it to produce the cyclic dinucleotide cGAMP (cyclic GMP-AMP). Both cGAMP and other pathogen-derived cyclic dinucleotides bind STING, which alters the conformation of the protein and allows it to facilitate the phosphorylation of interferon regulatory factor 3 (IRF3) by TANK-binding kinase 1 (TBK1). Interferon regulatory factor 3 phosphorylation induces protein dimerization and entry into the nucleus, where it acts as a transcription factor to drive interferon (IFN) expression. ER indicates endoplasmic reticulum.

Mentions: The binding of cyclic dinucleotides to STING causes a conformational change in the protein that allows it to act as a scaffold or adaptor protein for the kinase TANK-binding kinase 1 (TBK1) to phosphorylate a transcription factor known as interferon regulatory factor 3 (IRF3),34 which had previously been shown to be critical for IFN induction by cytosolic DNA.35 This phosphorylation event induces the dimerization of IRF3 and allows it to enter the nucleus where it can function as a transcription factor to drive the expression of type I IFNs and other gene targets.35–37 A schematic summarizing the STING-dependent production of IFN in response to viral and microbial DNA and cyclic dinucleotides is provided in Figure 1.


Crosstalk Between Apoptosis and Autophagy: Environmental Genotoxins, Infection, and Innate Immunity
Schematic of the stimulator of interferon genes (STING)– dependent innate immune response pathway. The infection of host cells by viruses and microbial pathogens results in the presence of nonself DNA or cyclic dinucleotides in the cytosol of the infected cells. The recognition of this DNA by the enzyme cyclic GMP-AMP synthase (cGAS) induces it to produce the cyclic dinucleotide cGAMP (cyclic GMP-AMP). Both cGAMP and other pathogen-derived cyclic dinucleotides bind STING, which alters the conformation of the protein and allows it to facilitate the phosphorylation of interferon regulatory factor 3 (IRF3) by TANK-binding kinase 1 (TBK1). Interferon regulatory factor 3 phosphorylation induces protein dimerization and entry into the nucleus, where it acts as a transcription factor to drive interferon (IFN) expression. ER indicates endoplasmic reticulum.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5392045&req=5

f1-10.1177_1179670716685085: Schematic of the stimulator of interferon genes (STING)– dependent innate immune response pathway. The infection of host cells by viruses and microbial pathogens results in the presence of nonself DNA or cyclic dinucleotides in the cytosol of the infected cells. The recognition of this DNA by the enzyme cyclic GMP-AMP synthase (cGAS) induces it to produce the cyclic dinucleotide cGAMP (cyclic GMP-AMP). Both cGAMP and other pathogen-derived cyclic dinucleotides bind STING, which alters the conformation of the protein and allows it to facilitate the phosphorylation of interferon regulatory factor 3 (IRF3) by TANK-binding kinase 1 (TBK1). Interferon regulatory factor 3 phosphorylation induces protein dimerization and entry into the nucleus, where it acts as a transcription factor to drive interferon (IFN) expression. ER indicates endoplasmic reticulum.
Mentions: The binding of cyclic dinucleotides to STING causes a conformational change in the protein that allows it to act as a scaffold or adaptor protein for the kinase TANK-binding kinase 1 (TBK1) to phosphorylate a transcription factor known as interferon regulatory factor 3 (IRF3),34 which had previously been shown to be critical for IFN induction by cytosolic DNA.35 This phosphorylation event induces the dimerization of IRF3 and allows it to enter the nucleus where it can function as a transcription factor to drive the expression of type I IFNs and other gene targets.35–37 A schematic summarizing the STING-dependent production of IFN in response to viral and microbial DNA and cyclic dinucleotides is provided in Figure 1.

View Article: PubMed Central - PubMed

ABSTRACT

Autoimmune disorders constitute a major and growing health concern. However, the genetic and environmental factors that contribute to or exacerbate disease symptoms remain unclear. Type I interferons (IFNs) are known to break immune tolerance and be elevated in the serum of patients with autoimmune diseases such as lupus. Extensive work over the past decade has characterized the role of a protein termed stimulator of interferon genes, or STING, in mediating IFN expression and activation in response to cytosolic DNA and cyclic dinucleotides. Interestingly, this STING-dependent innate immune pathway both utilizes and is targeted by the cell’s autophagic machinery. Given that aberrant interplay between the apoptotic and autophagic machineries contributes to deregulation of the STING-dependent pathway, IFN-regulated autoimmune phenotypes may be influenced by the combined exposure to environmental carcinogens and pathogenic microorganisms and viruses. This review therefore summarizes recent data regarding these important issues in the field of autoimmunity.

No MeSH data available.


Related in: MedlinePlus